Cancer progression and dissemination is due to adaptation of tumor cells to internal immune defenses and to external therapy. Thus, to reduce the public health burden due to cancer, it is necessary to understand the molecular basis of this process of adaptation. We recently found that in the course of both immune and drug selection, tumor cells undergo evolution towards gain of Nanog, a homeobox transcription factor pivotal for the self-renewal of pluripotent stem cells. We reported that Nanog expression in tumor tissue correlates with clinical prognosis. Furthermore, we found that Nanog converts tumor cells into a stem-like state and enables them to escape immune control through the Tcl1a-Akt pathway. Since the stem-like state permits indefinite self-renewal of cells, and since the Akt pathway coordinates the activation of a host of pro-survival signals, we reason that Nanog also confers drug resistance to tumor cells. We hypothesize that gain of Nanog underlies adaptation of tumor cells to host immune defenses as well as to therapy, and thus may represent a major driving force for cancer progression. As we have already established the role of Nanog in immune escape, the purpose of the current project is to investigate the role of Nanog in drug resistance. Our specific aims are to: (1) characterize the evolution of tumor cells towards Nanog expression and gain of a stem-like phenotype under drug selection by chemotherapy; (2) characterize the role of Nanog in conferring drug resistance to tumor cells; and (3) characterize the molecular mechanisms through which Nanog mediates drug resistance in tumor cells. The successful implementation of this project will be significant for several reasons. First, it reveals Nanog as molecular link between the stem-like state and drug resistance in tumor cells. This insight would directly lead to more successful choice of therapy and management of disease in cancer patients. Second, by identifying the Nanog-Tcl1a-Akt pathway as a gateway to both immune escape and drug resistance, this study sheds light on the process of cancer adaptation. Third, this project introduces a new approach to cancer chemotherapy. In particular, this study will prove the principle that the transcription network of stem cells can be rationally targeted to overcome the problem of cancer drug resistance. Based on these reasons, we believe this study will greatly advance our knowledge of cancer biology and have strong public health impact.